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Fisetin Enhances Behavioral Performances and Attenuates Reactive Gliosis and Inflammation During Aluminum Chloride-Induced Neurotoxicity

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Abstract

Aluminum (Al) is an environmental neurotoxin that affects cerebral functions and causes health complications. However, the role of Al in arbitrating glia homeostasis and pathophysiology remains obscure. Astrocyte, microglia activation (reactive gliosis), and associated inflammatory events play a decisive role in neurodegeneration and may represent a target for treating neurodegenerative disorders. In this study, we have analyzed the role of aluminum chloride (AlCl3) in causing reactive gliosis in the brain of mice and the ability of fisetin, a flavonoid to attenuate reactive gliosis and neuronal inflammation. Reports suggest that fisetin exerts antioxidant and anti-inflammatory actions. Fisetin at a dose of 15 mg/kg body weight was orally administered, daily (pre-treated for 4 weeks before AlCl3 induction and co-treated until experimental period of 8 weeks) to mice induced with AlCl3 (200 mg/kg b.wt./day/8 weeks, orally). Administration of AlCl3 developed behavioral deficits, triggered lipid peroxidation (LPO), compromised acetylcholine esterase (AChE) activity, and reduced the levels of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and reduced glutathione (GSH), and caused histologic aberrations. These effects were accompanied by increased expressions of Glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1. Pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1β, inducible nitric oxide synthase, were increased upon AlCl3 administration. AlCl3-induced alterations in the activities of SOD, CAT, GST, AChE and levels of GSH, LPO, activity of AChE, behavioral deficits, histologic aberrations, reactive gliosis, and inflammatory niche were attenuated on treatment with fisetin. Collectively, our results indicate that fisetin exerts neuroprotection against AlCl3-induced brain pathology.

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Acknowledgments

This work is supported in part by a major grant in neurosciences awarded to GS from Department of Science and Technology (DST), New Delhi, Govt. of India. We thank Dr. Niranjali Devaraj, Professor & Head, Department of Biochemistry, and Dr. H. Devaraj, Professor, Department of Zoology, University of Madras, Guindy campus for their helpful discussions in doctoral committee meeting of DP.

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The authors declare no conflict of interest.

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  1. Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai, 600025, Tamilnadu, India

    Dharmalingam Prakash, Kulasekaran Gopinath & Ganapasam Sudhandiran

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  1. Dharmalingam Prakash
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  2. Kulasekaran Gopinath
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Correspondence to Ganapasam Sudhandiran.

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12017_2012_8210_MOESM1_ESM.jpg

Supplementary Fig. 1 shows the effect of fisetin on hanging wire test upon AlCl3-induced neuromuscular dysfunction. Graph shows the total time spent in seconds (S) by the animals in the control and experimental groups to hang under the grid. Aluminum chloride (AlC3)-induced mice exhibited significantly low latency to fall in hanging wire test. Treatment with fisetin [pre-treatment (PT) and co-treatment (CT)] showed an improved performance in the hanging wire test. Hypothesis testing method included two-way analysis of variance (ANOVA) followed by post hoc Tukey’s test. Results were expressed as Mean ± SD; given as statistically significant at p<0.05; compared with (a): group 1, (b): group 2, (c): group 3 and, (d): group 4 (JPEG 366kb)

12017_2012_8210_MOESM2_ESM.jpg

Supplementary Fig. 2 shows the effect of fisetin on gait performances upon AlCl3-induced behavioral deficits in mice. Front paws were colored with tomato red, and the hind paws were colored with dark green (non-toxic water colors). Representative foot print patterns of control and experimental groups of mice are shown. In particular, three parameters have been recorded. Stride length (cm), sway length (cm), and stance length (cm). Qualitative analyses of foot prints showed significant differences in the stride, sway, and stance lengths. Disoriented walking patterns in Aluminum chloride (AlCl3)-induced mice are noticed form increases stride to stance length, which is typically abnormal as compared with control. Treatment with fisetin [pre-treatment (PT) and co-treatment (CT)] significantly improved the gait performance in AlCl3-induced mice. Hypothesis testing method included two-way analysis of variance (ANOVA) followed by post hoc Tukey’s test. Results were expressed as Mean ± SD; given as statistically significant at p<0.05; compared with (a): group 1, (b): group 2, (c): group 3, and (d): group 4 (JPEG 1711kb)

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Prakash, D., Gopinath, K. & Sudhandiran, G. Fisetin Enhances Behavioral Performances and Attenuates Reactive Gliosis and Inflammation During Aluminum Chloride-Induced Neurotoxicity. Neuromol Med 15, 192–208 (2013). https://doi.org/10.1007/s12017-012-8210-1

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